Researchers have recently discovered that cyclic adenosine 3′,5′-monophosphate (cAMP), which acts as an intracellular second messenger, controls the activity of inflammatory cells, such as lymphocytes, neutrophils, eosinophils, mast cells, etc. It is known that cAMP is degraded to 5′-AMP, which does not act as a messenger, by the action of phosphodiesterase (PDE), and that PDE adjusts the intracellular cAMP concentration. Since PDE has such a close relationship with the intracellular cAMP concentration, controlling PDE activity is believed to be effective against diseases for which therapeutic effects are expected to be exhibited by controlling the increase or decrease of the cAMP concentration (see Trends Pharmacol. Sci. 18: 164-170, 1997 and Immunopharmacology 47: 127-162, 2000).
Eleven types of PDE isozymes (PDEs 1 to 11) are known, and their in vivo distributions are known to vary among different tissues (see J. Allergy. Clin. Immunol. 108: 671-680, 2001 and Mol. Pharmacol. 64: 533-546, 2003). Reportedly, inhibitors specific to PDE4 suppress the functions of inflammatory cells, and are believed to be useful against conjunctivitis, asthma and like inflammatory allergic diseases, and multiple sclerosis, articular rheumatism and like autoimmune diseases (see Am. J. Respir. Crit. Care. Med. 157:351-370, 1998; Monaldi. Arch. Chest Dis. 57: 48-64, 2002; Arzneimittelforschung 44: 163-165, 1994; Eur. J. Pharmacol. 229: 45-53, 1992; Inflammation 17: 25-31, 1993; Nat. Med. 1: 244-248, 1995; J. Neuroimmunol. 79: 54-61, 1997; Clin. Exp. Immunol. 100: 126-132, 1995; Clin. Exp. Immunol. 108: 415-419, 1997; and J. Immunol. 159: 6253-6259, 1997).
Theophylline has been hitherto used as a PDE inhibitor for treating asthma. However, theophylline is known to nonspecifically inhibit various PDE isozymes, and thus inhibits not only PDE4 but also PDE3 and other isozymes. The inhibition of PDE3 is suspected of causing cardiotonic action and/or central action and producing positive inotropic and chronotropic effects in the heart (see Physiol. Rev. 76: 725-748, 1995). Therefore, the use of theophylline as a PDE inhibitor poses the problem of side effects.
Some compounds with specific inhibitory activity against PDE 4 have been reported (see Japanese Unexamined Patent Publication No. 1975-157360 and Japanese Unexamined Patent Publication No. 2003-64057). However, such PDE4 inhibitors have problems in that they bind to the high affinity rolipram binding site (HARBS) in the central nervous system and the alimentary canal and produce side effects, such as emesis induction and nausea, or have drawbacks in that they show insufficient PDE4 inhibitory activity. Thus, heretofore known PDE4 inhibitors have not been used clinically as therapeutic agents.
In view of this prior art, the development of a compound that effectively exhibits, without side effects, specific inhibitory activity against PDE4 is desired.